Controllable Hydrogen Sulfide Donors and Their Activity against Myocardial Ischemia-Reperfusion Injury

Hydrogen sulfide (H₂S), known as an important cellular signaling molecule, plays critical roles in many physiological and/or pathological processes. Modulation of H₂S levels could have tremendous therapeutic value. However, the study on H₂S has been hindered due to the lack of controllable H₂S releasing agents that could mimic the slow and moderate H₂S release <i>in vivo</i>. In this work we report the design, synthesis, and biological evaluation of a new class of controllable H₂S donors. Twenty-five donors were prepared and tested. Their structures were based on a perthiol template, which was suggested to be involved in H₂S biosynthesis. H₂S release mechanism from these donors was studied and proved to be thiol-dependent. We also developed a series of cell-based assays to access their H₂S-related activities. H9c2 cardiac myocytes were used in these experiments. We tested lead donors’ cytotoxicity and confirmed their H₂S production in cells. Finally we demonstrated that selected donors showed potent protective effects in an <i>in vivo</i> murine model of myocardial ischemia-reperfusion injury, through a H₂S-related mechanism